Opioid analgesics are often the treatment of choice for patients with severe pain. Besides its beneficial analgesia, opioids induce undesired side effects such as addiction, constipation, nausea and respiratory depression. Commonly administered drugs are the naturally occurring opiates isolated from opium or poppy straw, morphine and codeine, as well as semi-synthetic opioids derived from thebaine such as oxycodone and buprenorphine. The intense biological response is caused by their agonistic action to specific opioid receptors in the human body. In contrast, naltrexone, which is used for rapid detoxification of opioid dependent patients and methylnaltrexone are examples of opioid antagonists.
Goldberg and coworkers as well as more recently Cantrell and coworkers reported the syntheses of methylnaltrexone from naltrexone with appropriate methylating reagents such as methyl iodide or methyl bromide. [see, Goldberg et al., U.S. Pat. No. 4,176,186 and Cantrell et al., WO2004/043964]. Although quaternized morphine alkaloids occur as two diastereomers (the quaternized nitrogen represents an additional chiral center), both groups remained silent about the possible diastereomeric salts and reported a single isomer. In 2006 the first two “diastereoselective” syntheses of (R)- and (S)-methylnaltrexone were reported. The structure of (R)-methylnaltrexone (1) and (S)-methylnaltrexone (2) are shown in Scheme 1.

The reaction of naltrexone with methylbromide yielded predominantly (R)-methylnaltrexone [see, Doshan, H. D.; Perez, J. WO2006/127899], presumably the same compound as reported by Cantrell and Goldberg. Wang et al., [WO 2008/109156] have developed a further improved method by reacting naltrexone in an anhydrous aprotic dipolar solvent in the presence of 0.01-0.25 equivalents of HBr (relative to naltrexone) to suppress methylation of the C-3-hydroxide. In the same application, they achieved further improvement by first protecting the C-3-hydroxide with an acetyl group, quaternizing the acetyl-naltrexone with methyl bromide in N-methyl-2-pyrrolidone (NMP), and then removing the C-3-actyl group to give crude (R)-methylnaltrexone bromide (MNTX) in 83-87% molar yield.
Dlubala reported the conversion of naltrexone to methylnaltrexone bromide by first protecting the 3-O position with a benzyl group, reacting the benzyl-protected naltrexone with dimethylsulfate, followed by conversion of the resulting methylnaltrexone methylsulfate salt to the zwitterion, and then removal of the 3-O-benzyl protecting group and simultaneous precipitation of methylnaltrexone bromide by the addition of aqueous HBr, yielding also predominantly the (R)-methylnaltrexone [see Dlubala, WO 2008/034973, US 2008/0214817]. The addition of cyclopropylmethylenebromide to oxymorphone gave the (S)-isomer [see, Wagoner, H.; et al., WO2006/127898]. Not surprisingly, the (S)-isomer of methylnaltrexone exhibited different activities than those reported previously in the literature. These findings are in accordance with Bianchetti and coworkers, who studied the in vivo as well in vitro activity of three pairs of diastereoisomers of quaternary opioid antagonists derived from levallorphan, nalorphine, and naloxone. [Bianchetti, A. et al., Life Sciences 1983, 33(Suppl.1), 415-418]. Only the diastereomers prepared by methylation of the alkylated morphine derivative showed antagonistic activities.
The prior art methods for making methylnaltrexone of Goldberg et al., Cantrell et al., Doshan and Perez, Wang et al, and Dlubala all start from naltrexone. There are several possible routes to naltrexone (see Scheme 2) from biologically available raw materials (morphine, codeine, thebaine and oripavine), and all possible routes require a minimum of six chemical transformations, not including purifications of intermediates or the final product. Furthermore, when purifications of intermediates and/or the final product are included to meet the quality requirements of a drug substance, the molar yield of the final product relative to the biologically available raw material in each case falls below 30%. Cultivation of the poppies, which produce the biological raw materials, is tightly controlled, limiting their supply. The relatively high raw material costs and the manufacturing costs for each of the chemical conversions contribute to the cost of the final product.

A common feature of each of these routes is that at some point, the N-17 methyl group, which is common to each of the biological raw materials, is removed, a cyclopropylmethylene group is added, and a methyl group is added back in the final step. As noted earlier, quaternization of the nitrogen with a cyclopropylmethyl halide (at oxymorphone for example) gives the undesired S configuration at the nitrogen.
Even for the conversion of naltrexone to methylnaltrexone bromide, the number of chemical transformation steps ranges from one (Cantrell et al., Scheme 3), to four (Doshan and Perez; Scheme 4) to five (Dlubala, Scheme 5). In a very recent application, Wang et al., [WO 2008/109156] pointed out that the earlier one step Cantrell method gave a 60% molar yield of approximately 90% pure methylnaltrexone bromide which required a three step purification to give pure methylnaltrexone bromide. Wang et al developed a one-pot procedure, which comprises three chemical transformations (Scheme 6) and delivers methylnaltrexone in good yield (83-87% on a crude basis and 71% after purification).




Although the shortest route from a biological raw material requires a minimum of seven chemical transformations, the most efficient process to convert a biological raw material to methylnaltrexone via naltrexone requires a minimum of nine chemical transformations.
Representative examples of naltrexone syntheses are shown in Schemes 7-8. Scheme 7 shows a common commercial route for the manufacture of naltrexone is the alkylation of noroxymorphone in the presence of cyclopropylmethyl bromide and sodium hydrogen carbonate in dimethylacetamide at 65-69° C. for 6 hours to give naltrexone in 88.6% yield [Dlubala; US 2008/0214817 A1]. Naltrexone may also be manufactured from noroxymorphone by reductive alkylation with cyclopropylcarboxaldehyde [Goodwin et al., WO 2006/035195; Scheme 8]. The yield of naltrexone isolated as the hydrochloride salt ranged from 74-83%.


Noroxymorphone may in turn be prepared from morphine in 6 steps [Wallace, U.S. Pat. No. 5,112,975] or from thebaine via oxymorphone in 6 steps by the procedure described in Kavka, [U.S. Pat. No. 4,639,520]. Oxymorphone may also be prepared from oripavine using the procedure described by Wang et al, 2008118654/WO-A1, Dung et al., WO 2008072018 or Huang, WO 2008048711 and WO 2008048957.
Huang et al, [U.S. Pat. Nos. 5,869,669, 6,008,354 and 6013796] describe the synthesis of naltrexone from morphine and codeine in seven to nine chemical steps. In a subsequent application, Huang, [US 20080125592. assigned to Penick] describe the synthesis of naltrexone from oripavine in six chemical steps, combined into three unit operations.
In addition to the low overall conversion of biologically available raw materials and the number of chemical transformations, there remains the problem of the separation of the last traces of the S-isomer from the desired R-isomer of methylnaltrexone bromide to give a product containing levels not more than those specified by the ICH Guidelines for related substances (NMT 0.15%) in a drug substance. The preparations described by Doshan outlined in Scheme 6 gives a crude product containing 94.4% R-MNTX and 4.7% S-MNTX. After the first recrystallization from methanol, the product contained 98.0% R-MNTX and 1.5% S-MNTX. After a second recrystallization, the product contained 98.3% R-MNTX and 1.2% S-MNTX. On this basis, multiple recrystallizations with concomitant loss of R-MNTX would be necessary to achieve a product containing less than 0.15% S-MNTX.
The procedure of Wang et al. delivers crude methylnaltrexone containing 1.25-1.47% of the S-methylnaltrexone diastereomer, and 0.49-0.60% unreacted naltrexone and methylnaltrexone after purification containing 0.30-0.40% S-methylnaltrexone diastereomer, and 0.08-0.15% unreacted naltrexone.
Most preparations of buprenorphine in the literature involve a [4+2] cycloaddition reaction between thebaine or oripavine, or a protected derivative thereof, and methyl vinyl ketone, followed by reduction. A Grignard reaction is typically used to install the appropriate alkyl group at the C-7 pendant group and the installation of the N-cyclopropylmethylene group is typically performed later in the synthesis using a demethylation-realkylation reaction sequence. Representative examples of such preparations of buprenorphine are Zhong et al. [U.S. Pat. No. 7,119,100], Mannino et al. [US 2008/0312441], Bentley et al. [GB 1136214, U.S. Pat. No. 3,433,791], Huang et al. [US2008/0125592] and Zhang et al [Yiyao Gongye, Vol 2, 6-8, 1983].